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1.
Immunity ; 38(4): 742-53, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23601686

RESUMEN

MicroRNAs (miRNAs) regulate the function of several immune cells, but their role in promoting CD8(+) T cell immunity remains unknown. Here we report that miRNA-155 is required for CD8(+) T cell responses to both virus and cancer. In the absence of miRNA-155, accumulation of effector CD8(+) T cells was severely reduced during acute and chronic viral infections and control of virus replication was impaired. Similarly, Mir155(-/-) CD8(+) T cells were ineffective at controlling tumor growth, whereas miRNA-155 overexpression enhanced the antitumor response. miRNA-155 deficiency resulted in accumulation of suppressor of cytokine signaling-1 (SOCS-1) causing defective cytokine signaling through STAT5. Consistently, enforced expression of SOCS-1 in CD8(+) T cells phenocopied the miRNA-155 deficiency, whereas SOCS-1 silencing augmented tumor destruction. These findings identify miRNA-155 and its target SOCS-1 as key regulators of effector CD8(+) T cells that can be modulated to potentiate immunotherapies for infectious diseases and cancer.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Melanoma Experimental/inmunología , MicroARNs/metabolismo , Traslado Adoptivo , Animales , Apoptosis/genética , Proliferación Celular , Células Cultivadas , Citocinas/metabolismo , Citotoxicidad Inmunológica/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , MicroARNs/genética , ARN Interferente Pequeño/genética , Factor de Transcripción STAT6/metabolismo , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Replicación Viral/genética
2.
J Immunol ; 183(8): 5085-93, 2009 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-19801524

RESUMEN

Mice lacking epidermal Langerhans cells (LC) develop exaggerated contact-hypersensitivity (CHS) responses due to the absence of LC during sensitization/initiation. Examination of T cell responses reveals that the absence of LC leads to increased numbers of hapten-specific CD4 and CD8 T cells but does not alter cytokine expression or development of T regulatory cells. CHS responses and Ag-specific T cells are increased in mice in which MHC class II is ablated specifically in LC suggesting that direct cognate interaction between LC and CD4 cells is required for suppression. LC-derived IL-10 is also required for optimal inhibition of CHS. Both LC-derived IL-10-mediated suppression and full LC activation require LC expression of MHC class II. These data support a model in which cognate interaction of LC with CD4 T cells enables LC to inhibit expansion of Ag-specific responses via elaboration of IL-10.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Dermatitis por Contacto/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Interleucina-10/inmunología , Células de Langerhans/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Dermatitis por Contacto/metabolismo , Dinitrofluorobenceno/inmunología , Dinitrofluorobenceno/farmacología , Antígenos de Histocompatibilidad Clase II/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/inmunología , Proteínas de Homeodominio/metabolismo , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/metabolismo , Interleucina-10/metabolismo , Células de Langerhans/metabolismo , Ratones , Ratones Mutantes , Piel/inmunología , Linfocitos T Reguladores/metabolismo
3.
J Immunol ; 181(6): 3745-9, 2008 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-18768825

RESUMEN

Tissue-specific homing of effector and memory T cells to skin and small intestine requires the imprinting of specific combinations of adhesion molecules and chemokine receptors by dendritic cells in the draining lymph nodes. In this study, we demonstrate that CD8(+) T cells activated by Ag-pulsed bone marrow-derived dendritic cells were induced to express the small intestine homing receptors alpha(4)beta(7) integrin and chemokine receptor CCR9 in coculture with small intestinal epithelial cells. In contrast, in coculture with dermal fibroblasts the skin-homing receptor E-selectin ligand was induced. Interestingly, the imprinting of gut homing receptors on anti-CD3/anti-CD28 stimulated T cells was induced by soluble factors produced by small intestinal epithelial cells. Retinoic acid was identified as a crucial factor. These findings show that peripheral tissue cells directly produce homing receptor imprinting factors and suggest that dendritic cells can acquire their imprinting potential already in the peripheral tissue of origin.


Asunto(s)
Impresión Genómica/inmunología , Tejido Linfoide/inmunología , Tejido Linfoide/metabolismo , Receptores Mensajeros de Linfocitos/fisiología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Línea Celular , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Integrinas/biosíntesis , Integrinas/genética , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Tejido Linfoide/citología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Receptores CCR/biosíntesis , Receptores CCR/genética , Receptores Mensajeros de Linfocitos/biosíntesis , Receptores Mensajeros de Linfocitos/genética , Subgrupos de Linfocitos T/citología
4.
J Invest Dermatol ; 122(4): 945-52, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15102085

RESUMEN

UVB radiation has been shown to induce T cell tolerance most likely via modulation of the function of antigen-presenting cells like dendritic cells (DC), which are therefore of interest for vaccination therapy. Since little is known about the effects of UVB-irradiated dendritic cells (UVB-DC) on CD8(+) T cells, which are the dominant effectors in various allergic and autoimmune diseases, we have investigated the potential of low dose UVB (100-200 J per m(2)) irradiated bone marrow-derived dendritic cells to induce tolerance in murine CD8(+) T cells specific for the contact allergen trinitrophenyl (TNP) or for a viral peptide. In contrast to the previously reported successful tolerization of primed CD4(+) Th1 cells, neither naïve CD8(+) T cells nor CD8(+) Tc1 effector cells or established CD8(+) T cell clones could be tolerized by TNP-modified or peptide-pulsed UVB-DC in vitro or in vivo. We observed, however, a reduced capacity of UVB-DC to prime naïve CD8(+) T cells. Our data demonstrate an important difference in the susceptibility of CD4(+) and CD8(+) T cells for tolerance induction using low-dose UVB-irradiated DC and have implications for DC therapy of CD8(+) T cell-mediated diseases.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/efectos de la radiación , Tolerancia Inmunológica , Linfocitos T Reguladores/inmunología , Rayos Ultravioleta , Traslado Adoptivo , Animales , Células Cultivadas , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/inmunología , Epítopos , Ligandos , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/metabolismo , Trinitrobencenos
5.
PLoS One ; 9(8): e105266, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25121970

RESUMEN

Dendritic cells (DC) presenting tumor antigens are crucial to induce potent T cell-mediated anti-tumor immune responses. Therefore DC-based cancer vaccines have been established for therapy, however clinical outcomes are often poor and need improvement. Using a mouse model of B16 melanoma, we found that the route of preventive DC vaccination critically determined tumor control. While repeated DC vaccination did not show an impact of the route of DC application on the prevention of tumor growth, a single DC vaccination revealed that both the imprinting of skin homing receptors and an enhanced proliferation state of effector T cells was seen only upon intracutaneous but not intravenous or intraperitoneal immunization. Tumor growth was prevented only by intracutaneous DC vaccination. Our results indicate that under suboptimal conditions the route of DC vaccination crucially determines the efficiency of tumor defense. DC-based strategies for immunotherapy of cancer should take into account the immunization route in order to optimize tissue targeting of tumor antigen specific T cells.


Asunto(s)
Vacunas contra el Cáncer/inmunología , Células Dendríticas/inmunología , Inmunización , Melanoma Experimental/inmunología , Traslado Adoptivo , Animales , Antígenos Virales/genética , Antígenos Virales/metabolismo , Vacunas contra el Cáncer/administración & dosificación , Línea Celular Tumoral , Modelos Animales de Enfermedad , Expresión Génica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Inmunoterapia , Activación de Linfocitos/inmunología , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Transgénicos , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Mensajeros de Linfocitos/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Carga Tumoral , Proteínas Virales/genética , Proteínas Virales/metabolismo
6.
J Exp Med ; 211(1): 121-36, 2014 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-24378538

RESUMEN

Immune tolerance and activation depend on precise control over the number and function of immunosuppressive Foxp3(+) regulatory T (T reg) cells, and the importance of IL-2 in maintaining tolerance and preventing autoimmunity is clear. However, the homeostatic requirement for IL-2 among specific populations of peripheral T reg cells remains poorly understood. We show that IL-2 selectively maintains a population of quiescent CD44(lo)CD62L(hi) T reg cells that gain access to paracrine IL-2 produced in the T cell zones of secondary lymphoid tissues due to their expression of the chemokine receptor CCR7. In contrast, CD44(hi)CD62L(lo)CCR7(lo) T reg cells that populate nonlymphoid tissues do not access IL-2-prevalent regions in vivo and are insensitive to IL-2 blockade; instead, their maintenance depends on continued signaling through the co-stimulatory receptor ICOS (inducible co-stimulator). Thus, we define a fundamental homeostatic subdivision in T reg cell populations based on their localization and provide an integrated framework for understanding how T reg cell abundance and function are controlled by unique signals in different tissue environments.


Asunto(s)
Homeostasis/inmunología , Interleucina-2/metabolismo , Receptores CCR7/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Análisis de Varianza , Animales , Citometría de Flujo , Interleucina-2/inmunología , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Comunicación Paracrina/inmunología , Reacción en Cadena de la Polimerasa , Receptores CCR7/inmunología
8.
Methods Mol Biol ; 1032: 229-34, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23943457

RESUMEN

The bronchial epithelium has been increasingly recognized as an important immunomodulatory compartment in asthma and other lung diseases. Clara cells, which comprise the nonciliated secretory epithelial cells, are an important epithelial cell type with functions in the regulation of lung homeostasis and inflammation. Using naphthalene, Clara cells can be depleted within 24 h and regenerate by 1 month, hence, providing an easy method to study the impact of Clara cells on lung inflammation.


Asunto(s)
Asma/inmunología , Células Epiteliales/inmunología , Naftalenos/administración & dosificación , Neumonía/inmunología , Animales , Asma/inducido químicamente , Asma/patología , Linaje de la Célula/inmunología , Células Epiteliales/citología , Humanos , Ratones , Neumonía/inducido químicamente , Neumonía/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología
9.
J Clin Invest ; 120(8): 2767-81, 2010 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-20628202

RESUMEN

Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Asma/prevención & control , Glicoproteínas de Membrana/antagonistas & inhibidores , Proteínas de la Membrana/antagonistas & inhibidores , Receptores Virales/antagonistas & inhibidores , Animales , Asma/inmunología , Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Activación de Linfocitos , Glicoproteínas de Membrana/fisiología , Proteínas de la Membrana/fisiología , Ratones , Ratones SCID , Fosfatidilserinas/metabolismo , Receptores Virales/fisiología
11.
J Exp Med ; 205(7): 1559-65, 2008 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-18573908

RESUMEN

Cutaneous immune responses must be tightly controlled to prevent unwanted inflammation in response to innocuous antigens, while maintaining the ability to combat skin-tropic pathogens. Foxp3(+) regulatory T (T reg) cells are potent immune regulators and are found at high frequency in both human and mouse skin. Although T reg cells migrate to the skin and can dampen immune responses during experimentally induced inflammation or infection, the importance of cutaneous T reg cells for maintaining normal immune homeostasis in the skin has not been addressed. To selectively block T reg cell function in the skin, we restored the T reg cell compartment in Foxp3-deficient scurfy mice with cells whose ability to migrate to the skin was impaired because of targeted mutation of alpha-1,3-fucosyltransferase VII (Fut7). Although Fut7-deficient T reg cells were present at normal frequency and could function in all other tissues examined, these animals rapidly developed severe cutaneous inflammation. Thus, skin-resident T reg cell are essential for maintaining normal immune homeostasis at this site.


Asunto(s)
Movimiento Celular/inmunología , Factores de Transcripción Forkhead , Fucosiltransferasas/inmunología , Homeostasis/inmunología , Piel/inmunología , Linfocitos T Reguladores/inmunología , Animales , Movimiento Celular/genética , Dermatitis/enzimología , Dermatitis/genética , Dermatitis/inmunología , Fucosiltransferasas/genética , Fucosiltransferasas/metabolismo , Homeostasis/genética , Humanos , Ratones , Ratones Noqueados , Mutación , Piel/enzimología , Piel/patología , Linfocitos T Reguladores/enzimología
12.
J Immunol ; 180(11): 7574-81, 2008 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-18490759

RESUMEN

Francisella tularensis is a Gram-negative intracellular pathogen that causes the zoonosis tularemia. Because F. tularensis LPS causes weak TLR4 activation, we hypothesized that administration of a synthetic TLR4 agonist, aminoalkyl glucosaminide phosphate (AGP), would boost the innate immune system and compensate for reduced TLR4 stimulation. Intranasal administration of AGPs induced intrapulmonary production of proinflammatory cytokines and chemokines. Mice treated with AGPs before and after inhalation of Francisella novicida exhibited augmented cytokine and inflammatory responses to infection; reduced bacterial replication in lung, liver, and spleen; and increased survival, whereas all PBS-treated control mice died within 4 days of infection, all AGP-treated mice showed prolonged time-to-death, and 30-60% of AGP-treated mice survived. The protective effect of AGP was lost in mice lacking IFN-gamma. Long-term survivors developed specific Th1 splenocyte responses and specific Abs dominated by IgG2 isotypes. Survivors were fully protected from rechallenge with aerosolized F. novicida. Thus, preventive administration of AGP successfully modulated innate immune responses to aerosolized F. novicida, leading to protective immunity to pneumonic tularemia. This is the first report of the protective effect of a TLR ligand on resistance to F. novicida-induced pneumonic tularemia.


Asunto(s)
Glucosamina/análogos & derivados , Interferón gamma/metabolismo , Compuestos Organofosforados/administración & dosificación , Neumonía Bacteriana/inmunología , Receptor Toll-Like 4/agonistas , Tularemia/inmunología , Administración Intranasal , Animales , Lavado Broncoalveolar , Línea Celular , Citocinas/biosíntesis , Citocinas/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Francisella tularensis/crecimiento & desarrollo , Francisella tularensis/inmunología , Francisella tularensis/metabolismo , Glucosamina/administración & dosificación , Inmunidad Innata , Interferón gamma/inmunología , Hígado/microbiología , Pulmón/inmunología , Pulmón/microbiología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Neumonía Bacteriana/prevención & control , Bazo/microbiología , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismo , Tularemia/microbiología , Tularemia/prevención & control
13.
J Exp Med ; 205(9): 2151-62, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18725520

RESUMEN

Allergic contact hypersensitivity (CHS) is a T cell-mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rbeta2-deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12-independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) beta2, or both, we show that the concomitant absence of TLR4 and IL-12Rbeta2, but not the absence of TLR4 or IL-12Rbeta2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rbeta2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12-independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12-competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rbeta2-deficient mice, but not in germ-free TLR4/IL-12Rbeta2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands.


Asunto(s)
Dermatitis por Contacto/inmunología , Interleucina-12/metabolismo , Receptores Toll-Like/metabolismo , Alérgenos/química , Animales , Citocinas/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Biológicos , Transducción de Señal , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo
14.
Eur J Immunol ; 35(4): 1056-65, 2005 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15739162

RESUMEN

Tissue-selective homing is established during naive T cell activation by the tissue microenvironment and tissue-specific dendritic cells (DC). The factors driving induction and maintenance of T cell homing patterns are still largely unknown. Here we show that soluble factors produced during the interaction of T cells with CD11c(+) DC isolated from skin- or small intestine-associated tissues differentially modulate expression of the corresponding tissue-selective homing receptors (E-selectin ligands and alpha4beta7 integrin/CCR9, respectively) on murine CD8(+) T cells. Injection of tissue-specific DC via different routes induces T cells with homing receptors characteristic of the corresponding local tissue microenvironment, independent of the origin of the DC. These data indicate an important role for signals delivered in trans. Moreover, DC can reprogram the homing receptor expression on T cells previously polarized in vitro for homing to skin or small intestine. Importantly, skin-homing memory T cells stimulated directly ex vivo can also be reprogrammed by intestinal DC to a gut-homing phenotype. Our results show that tissue-selective homing receptor expression on effector and memory T cells is governed by inductive as well as suppressive signals from both DC and tissue microenvironments.


Asunto(s)
Células Dendríticas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Células de la Médula Ósea/inmunología , Integrina alfa4/inmunología , Cadenas beta de Integrinas/inmunología , Ratones
15.
J Immunol ; 172(2): 857-63, 2004 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-14707056

RESUMEN

The effector/memory T cell pool branches in homing subsets selectively trafficking to organs such as gut or skin. Little is known about the critical factors in the generation of skin-homing CD8+ T cells, although they are crucial effectors in skin-restricted immune responses such as contact hypersensitivity and melanoma defense. In this study, we show that intracutaneous, but not i.v. injection of bone marrow-derived dendritic cells induced skin-homing CD8+ T cells with up-regulated E-selectin ligand expression and effector function in contact hypersensitivity. The skin-homing potential and E-selectin ligand expression remained stable in memory phase without further Ag contact. In contrast, i.p. injection induced T cells expressing the gut-homing integrin alpha(4)beta(7). Although differential expression of these adhesion molecules was strictly associated with the immunization route, the postulated skin-homing marker CCR4 was transiently up-regulated in all conditions. Interestingly, dendritic cells from different tissues effectively induced the corresponding homing markers on T cells in vitro. Our results suggest a crucial role for the tissue microenvironment and dendritic cells in the instruction of T cells for tissue-selective homing and demonstrate that Langerhans cells are specialized to target T cells to inflamed skin.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Movimiento Celular/inmunología , Células Dendríticas/inmunología , Células Dendríticas/trasplante , Piel/inmunología , Piel/patología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/metabolismo , Quimiocinas CC/metabolismo , Células Dendríticas/patología , Dermatitis por Contacto/inmunología , Dermatitis por Contacto/patología , Memoria Inmunológica , Inflamación/inmunología , Inyecciones Intradérmicas , Inyecciones Intravenosas , Glicoproteínas de Membrana/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de Órganos/inmunología , Cloruro de Picrilo/administración & dosificación , Cloruro de Picrilo/inmunología , Receptores CCR4 , Receptores de Quimiocina/biosíntesis , Receptores de Factores de Crecimiento de Fibroblastos/biosíntesis , Sialoglicoproteínas , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
16.
J Immunol ; 173(5): 3178-85, 2004 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-15322178

RESUMEN

One of the unusual properties of chemically reactive haptens is their capacity to simultaneously generate immunogenic determinants for hapten-specific CD8(+) and CD4(+) T cells. Surprisingly, however, a clear dominance of CD8(+) effector T cells is observed in murine contact hypersensitivity to various haptens and upon T cell priming with hapten-modified APCs in vitro. In this study we show that trinitrophenyl-specific CD8(+) T cells actively prevent CD4(+) T cell priming in vitro. This process requires cell-cell contact and is dependent on the expression of Fas on the CD4(+) T cells. Our results reveal an important Fas-dependent mechanism for the regulation of hapten-specific CD4(+) T cell responses by CD8(+) T cells, which causes the dominance of CD8(+) effector T cells and the active suppression of a CD4(+) T cell response. Moreover, our demonstration of reduced contact hypersensitivity to trinitrophenyl in the absence of Fas, but not of perforin and/or granzymes A and B, underlines the important role of Fas as a pathogenetic factor for contact hypersensitivity.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Proteínas/fisiología , Receptores del Factor de Necrosis Tumoral , Trinitrobencenos/inmunología , Animales , Apoptosis/inmunología , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Dermatitis por Contacto/inmunología , Granzimas , Interferón gamma/metabolismo , Ratones , Ratones Noqueados , Proteínas/genética , Proteínas/inmunología , Serina Endopeptidasas/deficiencia , Serina Endopeptidasas/genética , Receptor fas
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